Patients ON Medication Research Articles

Dopamine restores cognitive motivation in Parkinson's disease.

Disorders of motivation, such as apathy, are common in Parkinson's disease, and a key feature of such disorders is a greater aversion to effort. In humans, the experience of cognitive effort is ubiquitous, and cognitive apathy has traditionally been considered distinct and separable from other subtypes. Surprisingly, however, the neurobiology of cognitive motivation is poorly understood. In particular, although dopamine has a well-characterized role in incentivizing physically effortful behaviour, a critical, unresolved issue is whether its facilitatory role generalizes to other domains. Here, we asked how dopamine modulates the willingness of patients with Parkinson's disease to invest cognitive effort in return for reward. We tested 20 patients with idiopathic Parkinson's disease across two counterbalanced sessions-ON and OFF their usual dopaminergic medication-and compared their performance to 20 healthy age-matched controls. We applied a novel task in which we manipulated cognitive effort as the number of rapid serial visual presentation streams to which participants had to attend. After training participants to ceiling performance, we then asked them to choose between a low-effort/low-reward baseline option, and a higher-effort/higher-reward offer. Computational models of choice behaviour revealed four key results. First, patients OFF medication were significantly less cognitively motivated than controls, as manifest by steeper cognitive effort discounting functions in the former group. Second, dopaminergic therapy improved this deficit, such that choices in patients ON medication were indistinguishable from controls. Third, differences in motivation were also accompanied by independent changes in the stochasticity of individuals' decisions, such that dopamine reduced the variability in choice behaviour. Finally, choices on our task correlated uniquely with the subscale of the Dimensional Apathy Scale that specifically indexes cognitive motivation, which suggests a close relationship between our laboratory measure of cognitive effort discounting and subjective reports of day-to-day cognitive apathy. Importantly, participants' choices were not confounded by temporal discounting, probability discounting, physical demand, or varying task performance. These results are the first to reveal the central role of dopamine in overcoming cognitive effort costs. They provide an insight into the computational mechanisms underlying cognitive apathy in Parkinson's disease, and demonstrate its amenability to dopaminergic therapy. More broadly, they offer important empirical support for prominent frameworks proposing a domain-general role for dopamine in value-based decision-making, and provide a critical link between dopamine and multidimensional theories of apathy.

High-frequency peripheral vibration decreases completion time on a number of motor tasks.

A recent theoretical account of motor control proposes that modulation of afferent information plays a role in affecting how readily we can move. Increasing the estimate of uncertainty surrounding the afferent input is a necessary step in being able to move. It has been proposed that an inability to modulate the gain of this sensory information underlies the cardinal symptoms of Parkinson's disease (PD). We aimed to test this theory by modulating the uncertainty of the proprioceptive signal using high‐frequency peripheral vibration, to determine the subsequent effect on motor performance. We investigated if this peripheral stimulus might modulate oscillatory activity over the sensorimotor cortex in order to understand the mechanism by which peripheral vibration can change motor performance. We found that 80 Hz peripheral vibration applied to the right wrist of a total of 54 healthy human participants reproducibly improved performance across four separate randomised experiments on a number of motor control tasks (nine‐hole peg task, box and block test, reaction time task and finger tapping). Improved performance on all motor tasks (except the amplitude of finger tapping) was also seen for a sample of 18PD patients ON medication. EEG data investigating the effect of vibration on oscillatory activity revealed a significant decrease in beta power (15–30 Hz) over the contralateral sensorimotor cortex at the onset and offset of 80 Hz vibration. This finding is consistent with a novel theoretical account of motor initiation, namely that modulating uncertainty of the proprioceptive afferent signal improves motor performance potentially by gating the incoming sensory signal and allowing for top‐down proprioceptive predictions.

Plantar cutaneous function in Parkinson’s disease patients ON and OFF L-dopa

While Parkinson’s disease (PD) is traditionally viewed as a motor disorder, there is mounting evidence that somatosensory function becomes affected as well. However, conflicting reports exist regarding whether plantar sensitivity is reduced in early-onset PD patients. Plantar sensitivity was assessed using monofilaments and a gold-standard, two-interval two-alternative forced choice vibrotactile detection task at both 30 and 250Hz. Lower-limb cutaneous reflexes were assessed by delivering continuous, sinusoidal vibration at 30 and 250Hz while recording muscle activity in Tibialis Anterior. We found no evidence of elevated plantar thresholds or dysfunctional lower-limb cutaneous reflexes in PD patients ON medication. We also found no acute effect of ceasing L-dopa intake on either plantar sensitivity or cutaneous reflexes. Our finding of intact cutaneous function in PD supports the further exploration of therapeutics that enhance plantar sensitivity to minimize postural instability, a source of considerable morbidity in this clinical population.

Altered cerebellar connectivity in Parkinson's patients ON and OFF L-DOPA medication.

Although nigrostriatal changes are most commonly affiliated with Parkinson's disease, the role of the cerebellum in Parkinson's has become increasingly apparent. The present study used lobule-based cerebellar resting state functional connectivity to (1) compare cerebellar-whole brain and cerebellar-cerebellar connectivity in Parkinson's patients both ON and OFF L-DOPA medication and controls, and to (2) relate variations in cerebellar connectivity to behavioral performance. Results indicated that, when contrasted to the control group, Parkinson's patients OFF medication had increased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity, whereas Parkinson's patients ON medication had decreased levels of cerebellar-whole brain and cerebellar-cerebellar connectivity. Moreover, analyses relating levels of cerebellar connectivity to behavioral measures demonstrated that, within each group, increased levels of connectivity were most often associated with improved cognitive and motor performance, but there were several instances where increased connectivity was related to poorer performance. Overall, the present study found medication-variant cerebellar connectivity in Parkinson's patients, further demonstrating cerebellar changes associated with Parkinson's disease and the moderating effects of medication.

Dopaminergic modulation of motor network dynamics in Parkinson's disease.

Although characteristic motor symptoms of Parkinson's disease such as bradykinesia typically improve under dopaminergic medication, deficits in higher motor control are less responsive. We here investigated the dopaminergic modulation of network dynamics underlying basic motor performance, i.e. finger tapping, and higher motor control, i.e. internally and externally cued movement preparation and selection. Twelve patients, assessed ON and OFF medication, and 12 age-matched healthy subjects underwent functional magnetic resonance imaging. Dynamic causal modelling was used to assess effective connectivity in a motor network comprising cortical and subcortical regions. In particular, we investigated whether impairments in basic and higher motor control, and the effects induced by dopaminergic treatment are due to connectivity changes in (i) the mesial premotor loop comprising the supplementary motor area; (ii) the lateral premotor loop comprising lateral premotor cortex; and (iii) cortico-subcortical interactions. At the behavioural level, we observed a marked slowing of movement preparation and selection when patients were internally as opposed to externally cued. Preserved performance during external cueing was associated with enhanced connectivity between prefrontal cortex and lateral premotor cortex OFF medication, compatible with a context-dependent compensatory role of the lateral premotor loop in the hypodopaminergic state. Dopaminergic medication significantly improved finger tapping speed in patients, which correlated with a drug-induced coupling increase of prefrontal cortex with the supplementary motor area, i.e. the mesial premotor loop. In addition, only in the finger tapping condition, patients ON medication showed enhanced excitatory influences exerted by cortical premotor regions and the thalamus upon the putamen. In conclusion, the amelioration of bradykinesia by dopaminergic medication seems to be driven by enhanced connectivity within the mesial premotor loop and cortico-striatal interactions. In contrast, medication did not improve internal motor control deficits concurrent to missing effects at the connectivity level. This differential effect of dopaminergic medication on the network dynamics underlying motor control provides new insights into the clinical finding that in Parkinson's disease dopaminergic drugs especially impact on bradykinesia but less on executive functions.

Impaired activation of somatosensory cortex as FMRI correlate of reduced dexterity in PD

WCN 2013 No: 1278 Topic: 2 — Movement Disorders Impaired activation of somatosensory cortex as FMRI correlate of reduced dexterity in PD T. Foki, W. Pirker, A. Geissler, D. Haubenberger, M. Hilbert, I. Hoellinger, M. Wurnig, J. Rath, J. Lehrner, S. Trattnig, E. Auff, R. Beisteiner. Department of Neurology, Medical University of Vienna, Vienna, Austria; MR Center of Excellence, Department of Radiology, Medical University of Vienna, Vienna, Austria; Department of Radiology, Medical University of Vienna, Vienna, Austria Background: Previously (1ab), the DOPA-resistant component of decreased dexterity in PD was called limb-kinetic apraxia (LkA). Our recent fMRI pilot study (2) investigating PD patients OFF medication suggested impaired activation of primary somatosensory cortex (SSC) as closely related to LkA. Both in the behavioral (1ab) and FMRI studies (2), coin rotation (CR, LkA task, target condition) was contrasted with simple finger tapping (FT, bradykinesia task, reference condition). FMRI signal changes were hence corrected for basic motor skills and represented activation particularly associated with dexterity. Based on the DOPA resistance of CR performance in (1ab), we hypothesized a reproducibility of impaired activation of the SSC ON medication. Objective: The objective of this study is to confirm dysfunction of SSC as closely related to DOPA-resistant dexterity deficits in PD. Patients and methods: According to the experimental setup (CR vs. FT) mentioned above, 10 PD patients performed the FMRI experiment in the ON as well as the OFF condition. 14 healthy controls performed the same experiment. Patients were compared to controls (SPM8). Results: Confirming our pilot study, we assessed decreased activation of the SSC in patients OFF medication compared to controls. In line with our study hypothesis, this finding was reproducible in patients ON medication compared to controls (p b 0.01, uncorr., k = 25 vox.). Comparing FMRI signals in the SSC between ON and OFF conditions, no differences could be assessed (lowering even to p b 0.05). Conclusions: Dexterity deficits in PD are linked to a dysfunction of the SSC. (1a) Gebhardt-et-al._MovDisord 2008;23 :1701-6. (1b) Quencer-et-al._Neurology 2007;68:150-1. (2) Foki-et-al._ExpNeurol 2010;225:416-22. doi:10.1016/j.jns.2013.07.405 Abstract — WCN 2013 No: 1269 Topic: 2 — Movement Disorders Subjective and objective alcohol responsiveness in different tremor disorders WCN 2013 No: 1269 Topic: 2 — Movement Disorders Subjective and objective alcohol responsiveness in different tremor disorders P. Schwingenschuh, M. Koegl-Wallner, U. Werner, T. Pendl, C. Ghadery, S. Seiler, K. Wenzel, R. Schmidt, P. Katschnig-Winter. Department of Neurology, Medical University of Graz, Graz, Austria Background: A few studies exist on the effect of alcohol in essential tremor (ET) and Parkinson s disease (IPD), but so far no systematic studies have been performed in other tremor syndromes. Nevertheless, a positive response to alcohol – commonly simply inquired by history – is used as supportive diagnostic criterion for ET. Objective: The objective of this study is to investigate if subjective/ objective alcohol responses distinguish a broad range of tremor disorders. Methods: (1) We assessed drinking habits and response of tremor to alcohol intake in 100 consecutive patients with arm tremor. (2) For a double-blind placebo-controlled oral alcohol test we recruited 12 patients with ET, 10 IPD, and 7 dystonic tremor (DT). The effect to alcohol/placebo was assessed at baseline and after 30/ 60/120 min by clinical rating scales and accelerometry. Results: (1) We investigated 44 patients with IPD, 22 ET, 20 DT, and 14 others. Of 77 patients drinking alcohol, 23 had no response, 26 had improvement, and 28 never paid attention. None of the evaluated parameters differed between the groups. (2) ET, IPD, and DT had a significant tremor improvement with placebo and alcohol. There were no significant between group differences. However, in the ET group there was a stronger objective effect of alcohol compared to placebo. Conclusions: Subjective alcohol response inquired by history may not be suitable as supportive diagnostic criterion for ET. Objectively, all investigated patients improved with alcohol. This effect seems to be truly alcohol related in ET only. doi:10.1016/j.jns.2013.07.406 Abstract — WCN 2013 No: 1258 Topic: 2 — Movement Disorders Exome sequencing analysis in familial progressive supranuclear palsy WCN 2013 No: 1258 Topic: 2 — Movement Disorders Exome sequencing analysis in familial progressive supranuclear palsy C. Bettencourt, A. Tucci, R. Ros, J. Lopez-Sendon, J. Hardy, J. Garcia deYebenes,H.Houlden. Department ofMolecularNeuroscience, UCL Institute of Neurology, London, UK; Department of Neurology, Hospital Ramon y Cajal, Madrid, Spain Background: Progressive supranuclear palsy (PSP) is a clinicopathological syndrome characterized by akinesia, supranuclear gaze palsy, Abstracts / Journal of the Neurological Sciences 333 (2013) e109–e151 e121

Dopamine and performance in a reinforcement learning task: evidence from Parkinson’s disease

The role dopamine plays in decision-making has important theoretical, empirical and clinical implications. Here, we examined its precise contribution by exploiting the lesion deficit model afforded by Parkinson’s disease. We studied patients in a two-stage reinforcement learning task, while they were ON and OFF dopamine replacement medication. Contrary to expectation, we found that dopaminergic drug state (ON or OFF) did not impact learning. Instead, the critical factor was drug state during the performance phase, with patients ON medication choosing correctly significantly more frequently than those OFF medication. This effect was independent of drug state during initial learning and appears to reflect a facilitation of generalization for learnt information. This inference is bolstered by our observation that neural activity in nucleus accumbens and ventromedial prefrontal cortex, measured during simultaneously acquired functional magnetic resonance imaging, represented learnt stimulus values during performance. This effect was expressed solely during the ON state with activity in these regions correlating with better performance. Our data indicate that dopamine modulation of nucleus accumbens and ventromedial prefrontal cortex exerts a specific effect on choice behaviour distinct from pure learning. The findings are in keeping with the substantial other evidence that certain aspects of learning are unaffected by dopamine lesions or depletion, and that dopamine plays a key role in performance that may be distinct from its role in learning.

Effect of Dopaminergic Medications on the Time Course of Explicit Motor Sequence Learning in Parkinson's Disease

The capacity to learn new motor sequences is fundamental to adaptive motor behavior. The early phase of motor sequence learning relies on the ventral and anterior striatal circuitry, whereas the late phase relies on the dorsal and posterior striatal circuitry. Early Parkinson's disease (PD) is mainly characterized by dopaminergic denervation of the dorsal and posterior striatum while sparing anterior and ventral regions. Dopaminergic medication improves dorsal and posterior striatum function by compensating for the loss of dopamine. However, previous work has shown that dopaminergic medication interferes with the ventral and anterior striatum function by overdosing this relatively intact structure in early-state PD. Here we test whether these effects are also observed over the time course of motor sequence learning. Fourteen PD patients ON and OFF dopaminergic medications and 11 healthy age-matched control participants performed an explicit motor sequence learning task. When sequence learning was compared across different learning phases in patients ON and OFF medication, a significant impairment associated with medication was observed in the early relative to later phases of learning. The rate of learning in the early phase measured trial by trial in patients ON medication was significantly slower than that in controls and when patients were OFF medication. No significant impairment was found in the later learning phases. These results demonstrate that dopaminergic medications may selectively impair early-phase motor sequence learning. These results extend and generalize the dopamine overdose effects previously reported for (antero)ventral striatum-mediated cognitive tasks to motor sequence learning.

Enhanced frontal function in Parkinson's disease

We investigated the role of dopamine in working memory by examining effects of withdrawing dopaminergic medication in patients with Parkinson's disease. Resistance to distraction during a delayed response task was abnormally enhanced in Parkinson's disease patients OFF medication relative to controls. Conversely, performance on a backward digit span test was impaired in these same Parkinson's disease patients OFF medication. Dopaminergic medication reinstated susceptibility to distraction and backward digit span performance, so that performance of Parkinson's disease patients ON medication did not differ from that of controls. We hypothesize that the enhanced distractor resistance and impaired backward digit span in Parkinson's disease reflects low dopamine levels in the striatum, and perhaps upregulated frontal dopamine levels. Dopaminergic medication may reinstate distractibility by normalizing the balance between striatal and prefrontal dopamine transmission.

Reversal learning in Parkinson's disease depends on medication status and outcome valence

We investigated the role of dopamine in distinct forms of reversal shifting by comparing two groups of patients with mild Parkinson's disease (PD), one ON and one OFF their normal dopaminergic medication. In accordance with our previous work, patients ON medication exhibited impaired reversal shifting relative to patients OFF medication. The present results extend previous studies by showing that the medication-induced deficit on reversal shifting was restricted to conditions where reversals were signaled by unexpected punishment. By contrast, patients ON medication performed as well as patients OFF medication and controls when the reversal was signaled by unexpected reward. The medication-induced deficit was particularly pronounced in patients on the dopamine D3 receptor agonist pramipexole. These data indicate that dopaminergic medication in PD impairs reversal shifting depending on the motivational valence of unexpected outcomes.